PATHOPHYSIOLOGY OF KIDNEY.KIDNEY INSUFFICIENCY Prof. Yu.I. Bondarenko Kidney is major organ that regulates maintenance of outcell liquid amount and persistance of constancy inner environmental in an organism Kidney is major organ that regulates maintenance of outcell liquid amount and persistance of constancy inner environmental in an organism The kidneys provide such main homeostatic parameters: The kidneys provide such main homeostatic parameters: isovolemia blood volume constancy isovolemia blood volume constancy isotonia osmotic pressure constancy isotonia osmotic pressure constancy isoionia ionic structure constancy isoionia ionic structure constancy isohydria concentration hydrogen ions constancy isohydria concentration hydrogen ions constancy Function of kidney includes three processes: Plasma filtration in glomerulus Selective canalicules reabsorbtion Hydrogen ions, ammonium and other substances secretion Structural and functional unit of a kidney, that provides these functions is nephrone NEPHRON NEPHRON Filtration disorder Glomerules filtration process is pushing of water and saltes through molecular sieve under action of arterial pressure in the capillaries It is passive process depending on hydrostatic pressure Filtration pressure displace liquid from capillary blood into canaliculus lumen and does not require energy Filtrational pressure, which predetermines glomerules filtrate derivation, is equal mm Hg Filtrational pressure in Bowmans capsula of healthy person is formated 120 ml of filtrate per 1 minutes, that is 180 l per one day The glomerules filtation can be decreased or increased Reasons of filtration decrease: 1. Hydrostatic pressure decrease in glomerules capillaries: in general decreasing of arterial pressure decrease (heart insufficiency, shock, collapse, hypovolemia), narrowing glomerules afferent arterioles (arterial hypertension, pain): aorta and kidneys arteries organic defeats (aorta coarctation, stenosic aorta atherosclerosis due to hypertonic illness), kidneys arteries thrombosis or embolism 2. Plasma oncotic pressure increase protein blood substitutes transfusion in large volumes 3. Intrakidney pressure increase canalicules block by cylinders or urinary tract by stones 4. Glomerulus filter disorder quantity functioning glomerulus decrease, glomerulus membrane thickening, an pores amount and diameter decrease, basal membrane glycoproteid components autoallergic damage. Consequences of filtration disorder The most characteristic manifestations of filtration disorder are: azotemia (accumulation in blood of nitrogen metabolic and blood residual nitrogen increase) renal azotemic acidosis owing to delay in an organism phosphates, sulfates and organic acids Increase of filtration resulting blood pressure increase excessive consumption water, decomplication edema or oncotic plasma pressure decrease (hepatitis, cirrhosis) Glomerulus filter permeability increased manifestations: proteinuria evacuation with urine of plasmatic proteins over physiological norm (30-80 mg/day) and appearance in urine protein fractions with molecular weight more than 70 kD hematuria issue erythrocytes into canalicules lumen and their appearance in urine. HEMATURIA presence of erythrocyts in urine (in norm erythrocytes dont pass through glomerular filter and absent in urine !!!) Hematuria renal (in glomerulonephritis) extrarenal (in nephrolithiasis, trauma of kidney) Erythrocyts that passed through basal membrane of glomerulus is changed, deformed as their shadow. It evidence of glomerular origin. Consequence of increased permeability of renal filter Reabsorption disorder The daily ultrafiltrate amount, which gets into canalicules makes equal 99 % of this volume is exposed to a converse absorption mainly in proximal canalicules Reabsorption of proteins, glucose, aminoacids, electrolytes, bicarbonates, phosphates and water almost completely are accomplished The reabsorbtion selectivity provides kidneys epithelium ability to reabsorp one substance and simultaneously prevents the other. This function is executed by specific molecules which are the carriers The dependence of reabsorbtion processes on molecules membrane carriers means the limited canaliculus epithelium ability to transport reabsorbed substance If the concentration of substance in glomerulus filtrat exceeds possibilities transport system, then given substance threshold exceeding Disorder of the canalicules function Disorder of the canalicules function is called as tubular insufficiency It may be hereditary or acquired Disorder of sodium and water reabsorbtion The increase of reabsorption is observed in fallowing case: hyperaldosteronism, oliguri stage of acute kidney insufficiency, reabsorption decrease hypoaldosteronism, diabetes insipidus Sodium and water reabsorption is decreased as a result of canalicules epithelium metabolism inhibition by some poisons, including medicines, in particular, mercury diuretics. Reabsorbtion is limited because of glomerulus filtrate osmotic active substances (glucose, urin), increase owing to that so-called osmotic diuresis arises (example, diabetes mellitus) The heavy disorders of sodium and water resorbtion arise in case dystrophic and inflammatory canaliculus epithelim changes, so canalicules lose the ability to liquid concentration and cultivation. Loss of concentration ability is called hypostenuria, relative density aqual in state changes within the limit of 1,006-1,012 (norma 1,002-1,035). If density urine is kept at 1,010 level and is not changed with influence water load, it is called isostenuria (monotone diuresis) Disorder of protein reabsorption The disorder of proteins reabsorption displays with tubular proteinuria Poisoning cadmium Hypoxia Burns Septicemia Tubular insufficiency is characterized by the increasing of contents in urine of albumins and other proteins with weight up to 40 kD (selective proteinuria). Dystrophic defeats canaliculus lead to appearence proteins with molecular weight more than 40 kD (unselective proteinuria) in urine The glucose reabsorbtion disorders Dayly norm of glucose loss with urine- up to 1g There are renal and extrarenal glucosuria. Renal glucosuria arises as a result : Hereditary anomalia membrane carriers deficiency enzymes hexokinase and glucose-6-phosphatase, which provide glucose canalicules reabsorption. Equired decrease of these enzymes activity in case of chronic poisonings with lead, mercury, uranium compounds. Experimentally it is possible to resynthesis by means of floridsine,which oppresses phosphorilation in canalicules cells. Extrarenal glucosuria stipulated hyperglycemia which exceeds renal threshold (9.0 10 mmol/l). More often it is observed due to diabetes mellitus. The inorganic phosphate and calcium disorder reabsorbtion have the hereditary character. Renal phosphate diabetes is manifested with phosphaturia, calciuria, rachitis, resistance to vitamin D, canalicules sensitiviby to parathormone increase (pseudohyperparathyroidism). Hereditary osteodystrophias are characterized with hypocalciemia, hypophosphatemia, parathormone canalicules resistance because of appropriate receptors absence ( pseudohyperparathyroidism) The aminoacids reabsorbtion disorder Renal aminoaciduria develops due to of the normal aminoacids contents in blood and is explained by hereditary transport or membrane molecules-carriers deficiency. Extrarenal aminoaciduria is observed in case of increase catabolism proteins (disintegration tumor, inflammation), phenylketonuria, cystinosis, hyperglycinemia Combined tubulopathy The most known example of such disorders is the Fankony syndrome. In basis of this symptomocomplex lies kidneys canalicules function generalized disorder. It includes glucosuria, aminoaciduria, phosphaturia, hypercalciuria, hypernatriuria, proteinuria, proximal renal canalicules acidosis with bicarbonaturia, rachitis with resistantion to vitamin D. Disoder of secretion The main manifestation canaliculus acidosis due to inhibition ammonium- and acidogenesis and secretion H+-ions. Hyperuricemia, which develops owing to urinary acid secretion disorder and lead to gout (renal form). Kidney functional disorders can be completed with their insufficiency. Acute renal insufficiency It is a clinical syndrome (ARI), which is characterized by significant and acute decrease of glomerular filtration rate (GFR) Normal GFR significance ml/mines Acute renal insufficiency develops, when GFR is reduced to 1-10 ml/mines Osmotic active substances in amount which is derivated easily excrete in volume water of 1,5-2 l (daily diuresis) for one day with the normal diet and normal metabolism out of organism The minimum quantity of liquid, from which they can still be excreted makes 500 ml Acute renal insufficiency is characterized by such disorder renal functions when diuresis is reduced to 500 ml. This state is called as oliguria If daily urine does not exceed 100 ml, takes place anuria Acute renal isufficiency Reasons of the acute renal insufficiency are divided into three groups prerenal, renal and postrenal Prerenal factors include: circulatting liquid decrease (traumatic shock, blood loss, burns, vomiting, diarrhea), dilatation of vessels and vessels capacity increase (sepsis, anaphylaxia), heart insufficiency (myocardium infarction) Reasons of ARI Renal factors include: ischemia of kidneys, action nephrotoxines (antibiotics, heavy metals, organic solvents, X-ray contrast substances), intravessels erythrocytes hemolysis, glomerulonephritis, states assosiated to pregnancy (septic abortion, eclampsia in pregnant, bleeding) Reasons of ARI Postrenal factors include: Ureters obstruction (canaliculus, blood clots, tumor) and urinal channel obstruction (prostat hypertrophy, carcinoma). Postrenal reasons of diuresis decrease are reduced of urine outflow due to obstruction of any level of urinary way. Clinical phases of ARI. Clinical phases of ARI. Initial phase is a period, which courses from lesion of kidneys untill oliguria development. It takes several hours (ischemia) up to about one week (after action nephrotoxine) Initial phase is a period, which courses from lesion of kidneys untill oliguria development. It takes several hours (ischemia) up to about one week (after action nephrotoxine) Oliguric phase is characterized by acute decrease of GFR. It course last several days up to several weeks (two weeks in average ). The patients perish just in this phase Oliguric phase is characterized by acute decrease of GFR. It course last several days up to several weeks (two weeks in average ). The patients perish just in this phase Diuretic phase is characterized by gradual increase of urine volume. Phase of recovery period, during which renal function completely are restored, though easy or moderate GFR decrease can be saved in some patients Diuretic phase is characterized by gradual increase of urine volume. Phase of recovery period, during which renal function completely are restored, though easy or moderate GFR decrease can be saved in some patients Acute renal insufficiency is accompanied by high death, data ischemic and traumatic form about % other form about % Acute renal insufficiency is accompanied by high death, data ischemic and traumatic form about % other form about % Chronical renal insufficiency ( CRI ) Symptoms chronical renal insufficiency develops in case GFR 25 % over norm The main reasons: primary glomerulus diseases (chronic glomerulonephritis) the primary canaliculus diseases (chronic pielonephritis, tuberculosis) vascular diseases (hypertonic illness, thrombosis, embolism) diffuse connective tissue diseases (sclerodermia, nodular periarteriitis) illness of metabolism (gout, diabetes mellitus), obstructive nephropathy (urolithiasis, hydronephrosis), hereditary anomalies ( kidneys polycystic) Pathogenesis of chronical renal failure Renal functions decrease arise due to decrease of acting nephrons amount The signs initial chronical renal insufficincy arise owing to decrease of acting nephrons mass to % The expressed clinic signs arise due to decrease of acting nephrons to % Further decrease of acting nephrons weight (is lower than 10 %) results in terminal kidneys insufficiency stage uremia Complications of renal failure Anemia is the most characterized sign of chronical renal insufficiency. Decrease of erythropoietin formation. Increase of erythrocytes hemolys. Uremia oppress bone marrow ability to erythropoietin reaction. Alimentary channel bleeding. Continuous loss blood result in deficiency iron which promotes anemia development. Thrombocylopathy. Chronical renal insufficiency in the patients have a qualitative changes of thrombocytes. It appears as bleeding duration increase. Complications of renal failure Heart is damaged owing to hypertension. The combination of hypertension, anemia, liquid overloading and acidosis promotes heart insufficiency development. In half of patients chronical renal terminal insufficiency stage pericarditis develops The lung damage is performed with so-called uremic pneumonitis, which is the stagnant phenomen in vessels of peritracheal Arterial hypertension is observed in 50 % of terminal chronical renal insufficiency stage. It arises is connected with hyperproduction renine,and synthesis decrease of vasodilatative prostaglandins, oppression limitation sodium excretion of extracellular liquid volume increase Gastrointestinal disorder anorexia, nausea, vomiting. The bleeding from alimentary channel is often phenomenon.Their source are the small surface ulcers, which bleeding slowly Uremic encephalopathy Sleepiness Inability to concentration Absent-mindness Amnesia Hallutinations Delirium Cramps Osteoporosis Decrease of phosphates excretion lead to increase their level in blood. Result hydrooxiapatite is derivation and ionized calcium level is decreased, thus it stimulates parathyroid glands. If GFR decrease below 25 % of norm, secondary hyperparathyreosis become obvious. Resorbtion of bones is increased and their density is decreased. When weight nephrones is less than 25 %, the 25-- vitamin D transformation to the active form 1,25 (OH)2-vitamin D transformation is decelerated. It is the reason of calcium delay absorbtion in alimentary channel Osteodistrophy It is includes such disorders: ) fibrosis-cystoses osteitis as result of secondary hyperparathyreosis; it appears subperiosteol bone resorbtion; b) osteomalation bones defeat which organic matrix mineralisation process mineralisation infringed; c) osteosclerosis bone density increase; d) osteoporosis bone weight decrease and microstructural, which increase bone fragility. Bones change are capable to cause destructive action on organism: Delay growth in children Painful fractures bones in adult Compressed necrosis of head femoris Skeleton deformation Calcification of arterial medial layer Skin calcification with intolerable itch Periarteriitis owing to calcium oxyapatitis precipitation, calcification Uremia Uremia is a term, which is used for chronical renal insufficiency in terminal phase. The majority of symptoms become well expressed in GFR ratio below than 10 ml/min. Uremic syndrome pathogenesis has become subject of intensive learning for a long time. The numerous attempts were made to identify substances, which are accumulated in renal insufficiency terminal stage and reach dangerous to the vital function. Uremic toxins is nitrogen metabolism products. 1. Urea; 2. Guanidine derivates (methylguanidine, guanidinsuccinic and guanidinacetative acids, kreatine and kreatinin); 3. Aromatic compounds (phenole, indole, aromatic amines); 4. Conjugated aminoacids, lowmolecular peptides. In uremia development significance is peptides hormones accumulation parathhormone, insuline, glucagone, gastrine, vasopressine, adrenocorticotropic and somatotropic hormones. In the kidneys is catabolysed 25 % of peptide hormones. Some effects is stipulated compounds deficiency, which are not synthesized in uremia. Examples erythropoietine and 1,25-dihydroxycholecalciferol deficiency. TO YOU !!! THANKS A LOT !!!